Project Summary/Abstract The Molecular Genetics Program has been continuously approved through the NCI CCSG since the USC Norris first received NCI designation over 35 years ago. This Program has always been distinguished nationally for its strength in DNA replication and DNA repair, with an emphasis on applying discoveries toward cancer chemotherapy. During the project period, Preet Chaudhary joined Michael Lieber as Co-Leader to add depth in translation and oversee a new theme on the molecular genetics of cancers associated with infection by HHV8, including the development of targeted therapies for the treatment of these cancers. The Program has three integrated aims: 1) DNA replication, cell cycle, and cell proliferation in genetic instability; 2) DNA repair and recombination in genetic instability; and 3) viral oncogenesis with an emphasis on HHV8. Lymphoid malignancies are used as a disease model used by Program members for all three aims. Members continue to be highly interactive within and across themes and across program boundaries. The 39 Program members, who come from three schools and 13 departments, have $11.4M in peer-reviewed funding (direct costs), of which 18% is from NCI, 61% from other NIH sources, and 8% from other peer-reviewed funding sources. The Program is highly productive with 439 publications of which 21% are inter-programmatic, 15% intra- programmatic and 25% inter-institutional. Program Leaders organize retreats and mini-symposia several times per year to cross-fertilize research within and across Programs while remaining watchful to ensure a high level of member crosstalk. This has led to high success in securing new P01s that are intra- and inter-programmatic, while also cross-cutting thematically. Examples include renewal of an NCI P01 on understanding human DNA polymerase active sites and development of new chemotherapeutics (Goodman, McKenna, Warshel), and a new NCI P01 on viral oncogenesis by KSHV (HHV8) (Jung, Feng, Gao). Members have been particularly successful in seeking new cancer drug therapies, which has been achieved with the Translational and Clinical Sciences Program.